Effects of chronic oral administration of the antidepressant drugs imipranine, zimelidine and mianserine will be studied on 5-HT neuron systems and their transmitter-identified afferent input using newly developed morphometrical procedures as well as quantitative receptor autoradiography. Also the substance P immunoreactive cell groups and TRH immunoreactive cell groups within the medulla oblongata will be morphometrically characterized in a similar way. After morphometrical characterization of these types of transmitter-identified nerve cell groups the influence of chronic antidepressants on their cell body and cell group parameters will be studied. Also transmitter-identified afferent inputs to the raphe nuclei innervating the 5-HT nerve cell groups, such as the catecholamine afferents, enkephalin afferents and substance P afferents will be analyzed by performing density maps of the monoamine and neuropeptide afferents and relate them to the morphometrical features of the 5-HT cell body groups and by studying their modulation by chronic antidepressant treatment. By means of the radioactive 2-deoxy-d-glucose method a metabolic map of the 5-HT raphe nuclei will be made and this map will be related to the morphometrical maps of the 5-HT nerve cell groups. Also it will be studied if chronic antidepressant treatment can modulate the localization of metabolic (functional) activity in the various raphe nuclei. Effects of chronic antidepressant treatment on the 5-HT and the substance P immunoreactive nerve cell groups and terminal networks will also be tested by means of quantitative immunocytochemistry using monoclonal substance P antiserum and a 5-HT antiserum. By means of newly developed quantitative methodologies to determine the entity of coexistence it will be studied how chronic antidepressant treatment may modulate the entiry of coexistence of 5-HT, substance P- and TRH-like immunoreactivity in the bulbospinal 5-HT neurons. Finally, by means of quantitative autoradiography the distribution and characteristics of 3H-neuropeptide and 3H-monoamine binding sites of various types will be evaluated in relation to the 5-HT neurons as well as their modulation by chronic antidepressants. These new methodologies and the experiments described above will open up new aspects on the possible mechanisms of action of -antidepressant compounds.